Abstract

Spinal Cord Injury (SCI) is a devastating condition that often leads to permanent functional and neurological deficits in injured individuals. One of the most overlooked consequences of spinal cord injury is sexual functions, such as erectile and ejaculatory dysfunction. Mesenchymal stem cells (MSCs) have been reported as adjunctive treatment to SCI cases. Some animal studies reported both functional and conductivity improvement after MSCs application. Clinical studies on human has also been conducted in small basis, but so far showed equivocal results.

Keywords

Erectile dysfunction, spinal cord injury, mesenchymal stem cells

Case Illustration

A thirty-seven-year-old male patient was
riding a motorcycle at moderate speed (30-40
km/hour) when he was hit by a car from the
right side six years before visiting us in our spine
clinic. He had no sensory or motor function
at the level of Th7 and below. He was also
examined for Somatosensory Evoked Potential
(SSEP), which found a total functional lesion
of dorsal horn of spinal cord at both sides of
C7-Th12 vertebrae (FIGURE 1). Motor
Evoked Potential (MEP) examination revealed
that central interneuron activity in right side
was lower than left side. He also complained of
erectile dysfunction and retrograde ejaculation,
which was measured by Erection Hardness
Score (EHS) and International Index of Erectile
Function (IIEF). At the baseline, he had EHS
of 1 (penis is larger and not hard) and IIEF of
8 (moderate erectile dysfunction). His poor
erectile function was also showed by rigiscan
that stated an organic erectile dysfunction due
to neurological problem. In addition, he had no
ejaculation.

Here, we had planned a cycle of stem cell
application, consisting of three consecutive
injections with interval of 2 weeks. For first
injection, we supplied 10 × 106 cells via
intravenous route, 16 × 106 cells via intrathecal
route at inter laminar space of vertebrae lumbar 3 and 4, and 16 × 106 cells via intra-lesion route
at level vertebrae thoracic 7. The second and
third injection was given16 × 106 cells by intralesion
fashion. The stem cells were cultured
from his own bone marrow.

At one-month follow-up, his erection
function improved by EHS score of 2 (Penis
is hard, but not hard enough for penetration)
and 13 (Mild to moderate erectile dysfunction)
respectively (TABLE 1). Clinically there were
also sensory improvement, Normal sensory
function was found at the level of Th7-8 and
hypoesthesia was found at the level of Th9 and
below. At this time, minimally active movement
of the hip flexor muscles and palpable contraction
of the knee extensor muscles were also noted.
At three-month follow-up, he experienced a
successful ejaculation, albeit an inadequate
one. He had no orgasm. Moreover, his erectile
function improved further, as showed by EHS
score of 3 (Penis is hard enough for penetration,
but not completely hard) and IIEF score of 21
(Mild erectile dysfunction).

Evaluation

Baseline

1 month

3 months

Sensory function (SSEP)

Total functional lesion of bilateral dorsal horn of C7-Th12

N/A

Total functional lesion of bilateral dorsal horn of C7-Th12

Motor function (MEP)

Central interneuron activity in right side is lower than left side

N/A

Central interneuron activity in right and left side is moderate

Erectile function

EHS

IIEF

1
8

2
13

3
21

Ejaculation function

No ejaculation

No ejaculation

Normal ejaculation

Table 1: Nerve and erectile function follow up.

Discussion

Long tracts of the central nervous system
between the cortex and sacral spinal cord need
to be intact for the spinal cord and preservation
of his type of responsiveness in men with low
spinal cord physiological sexual function. The
cerebral centers which have important role
in erection mechanism have not yet been well
defined. Spinal cord damage can inhibit the
transmission of impulses down the spinal cord
and through the peripheral and autonomic
nervous system to the genitalia.

Erection is a complex neuro-vascular event.
In peripheral innervation, the pelvic plexus has a
great role as a junction for efferent nerves to the
structures involved in erection and ejaculation.
There are three sets of neurons at the spinal cord
which innervate the sexual organs involved in
erection and ejaculation, namely thoracolumbar sympathetic, sacral parasympathetic, and
somatic. The brain has an excitatory or inhibitory
effect on the process of erection and ejaculation
by the presence of cerebral descending pathway.

There are several structures responsible for
three types of erection: psychogenic, reflexogenic,
and nocturnal. Psychogenic erection can be
achieved by audiovisual stimuli or fantasy. The
brain sends impulses to modulate the spinal
erection centers (T11-L2 and S2-S4) to activate
the erectile process. While, reflexogenic erection
is achieved by tactile stimuli to the genital
organs. These impulses modulate the spinal
erection centers and then follow the ascending
tract, resulting in sensory perception. Some
other impulses activate the autonomic nuclei
to activate the cavernous nerves to the penis
to induce erection. Reflexogenic erection is
preserved in patients with upper spinal cord
injury. Nocturnal erection happens mostly
during Rapid-Eye-Movement (REM) sleep.

In the present case, spinal cord injection led
to improvement on both erectile and ejaculatory
function of the patient, as soon as 1-month
follow-up. Several mechanisms for recovery
have been proposed, including replacement of
oligodendrocytes or neurons, remyelination of
spared axons, restoration of neuronal circuitry,
enhanced preservation of host neuronal and glial
cells, increased expression of neurotrophins/
cytokines by transplanted or host cells,
promotion of angiogenesis, bridging of cysts
or cavities, reduced inflammation or gliosis,
stimulation of endogenous precursor cells, and
creation of a favorable environment for plasticity
and axonal regeneration (FIGURE 2). In most
studies, the exact mechanisms of improvement
were not completely defined.

Figure 2: Potential mechanisms of spinal cord
repair following stem cell transplantation
include replacement of oligodendrocytes or
neurons by transplanted cells (shown in green),
remyelination of spared axons, restoration of
neuronal circuitry by a new synapse, enhanced
preservation of host neuronal and glial cells,
promotion of angiogenesis, bridging of the
cyst/cavity, reduction of inflammation or
gliosis, stimulation of endogenous precursor
cells, and creation of a favorable environment
for plasticity and axonal regeneration.

It has been known that sexual function
in different stages after SCI and the types of
erections depend mainly on the completeness of
the injury and the level of neurological damage.
The patient in this case report had a complete SCI at the level of Th7 vertebrae. He had poor
remaining erectile and ejaculatory function, as
depicted by initial EHS and IIEF score as well
as rigiscan examination. For complete SCI,
both erectile and ejaculatory problems was
mainly associated with neurologic injury that
causes autonomic control dysfunction as well as
inadequate brain stimulus toward effector side
[1,2].

The residual erectile capacity of spinal cord
injured patients is a function of the remaining
neural connections within the genital system.
The anatomical connections within the genital
system include two nervous pathways, one
originating from the sacral segments S2, S3, S4
of the spinal cord and involving the pudendal
and pelvic nerves, the other originating from
the thoracic-lumbar segments T11, T12, L1, L2
and involving the hypogastric, sympathic, and
pelvic nerves.

The first of these two pathways, namely the
sacral pathway, has been studied extensively at
the anatomical and physiological level, as well
as at the animal and human level. At the spinal
cord injury level it has been demonstrated
that the thoracic-lumbar (TL) pathway could
convey penile responses forom stimulation of
higher CNS structures in the absence of reflex
activity from the sacral pathway. At the animal
level, cauda equine lesions of S1 completely
interrupted reflex activity from the sacral
pathway, including bladder function and penile
responses to genital stimulation. Nevertheless,
85% of the animals maintained penile responses
to stimulation of a hypothalamic area, a support
for the hypothesis of a role for the TL pathway
in mediating erection. At the human level, 80%
of the subjects whose lesions interrupted the
sacral pathway maintained erectile responses
to psychogenic stimulation. These findings,
along with the previous ones, further emphasize
the complementary role of the TL pathway in
paraplegic subjects who have lost function from
the sacral pathway. The overall results show that
very few spinal cord injured subjects suffer from
complete impotence. The vast majority maintain
a residual erectile capacity upon which a sexual
rehabilitation programme could be build.

Patients with sacral SCI retain psychogenic
erectile ability even though reflexogenic erection
is abolished. These cerebrally elicited erections
are found more frequently in patients with lower
motor neuron lesions below T12. However, no
psychogenic erection occurs in patients with
lesions above T9, as seen in our patient, because
the efferent sympathetic outflow is located at the
levels T11 and T12 [3]. Also reported, in these
patients with psychogenic erections, lengthening
and swelling of the penis are observed but
rigidity is insufficient [4].

He experienced immediate improvement
on both erectile and ejaculatory manifestations,
slightly before improvement on sensory and
motor function. There were only few cases
of chronic SCI that found its way to clinical
improvement [5] and furthermore, to our
knowledge, there was still no published article
describing the recovery of sexual function
of SCI patients. Furthermore, it was widely
known that both parasympathetic and
sympathetic component in the spinal cord are
located centrally. The patient had complete
transection of his spinal cord with persistent cord compression and focal atrophy. Even
though it was not proved by imaging modality,
there was an immediate recovery of sexual
functions, which is known to be driven mainly
by autonomic functions. From this finding,
we hypothesized that the prompt recovery of
erectile and ejaculatory functions in our patients
was due to central healing of spinal cord that
involves sacral parasympathetic pathway.

The sympathetic and parasympathetic
nervous systems act in synergy to activate
physiological events occurring during ejaculation.
Both sympathetic and parasympathetic tones
are under the influence of sensory genital and/or
cerebral erotic stimuli integrated and processed
at the spinal cord level.

Sympathetic, parasympathetic, and somatic
nerves originating in lumbosacral spinal nuclei
command the peripheral anatomical structures
responsible for ejaculation. Sensory afferents
originating in genital areas are integrated at the spinal and brain levels. Activity of spinal
preganglionic and motor neurons is under the
influence of peripheral and supraspinal inputs.

Recently, there was a study about Spinal
Ejaculation Generator (SEG) which has been
identified to have a pivotal role in the control of
ejaculation. Galaninergic neurons were mostly
located between L2 and L5 segments in medial
lamina VII, with a maximal density within
L4. In addition, galaninergic neuron density
was found higher in L3 and L4 segments in
men as compared to women supporting sexual
dimorphism. In the patients’ cohort, injury
of L3-L5 segments was the sole independent
predictor for failure of Penile Vibratory
Stimulation (PVS) to induce ejaculation.

Conclusion

This report provided a novel insight to
regenerative model of chronic SCI patients
as well as further addition of successful MSCs
treatment for chronic SCI cases.